心衰病人心房顫動治療新策略

1、心衰病人心房顫動治療新策略心衰病人心房顫動治療新策略心房選擇性抗房顫藥物展望心房選擇性抗房顫藥物展望吡西卡尼西苯唑啉普羅帕酮丙吡胺氟卡尼肺靜脈電隔離消融&起搏孤立性 AF陣發(fā)性 AF電復律控制心率芐普地爾+/-阿普林定索他洛爾胺碘酮 (口服)首選房顫持續(xù)時間短第二 , 第三選擇孤立性孤立性AF心律控制策略心律控制策略Circ J. 2008 ; 72 (Suppl.IV) : 15811638持續(xù)性AFM2A1Na/KATPase泵CaKI f受體吡西卡尼氟卡尼西苯唑啉普羅帕酮丙吡胺slowmedfastNa通道藥物A 作用強度( 低, 中, 高) AAAA 抗心律失常藥物作用特征Og

2、awa S: JPN. J. ELECTROCARDIOLOGY 17(2), 191, 1997控制心率阿普林定芐普地爾索他洛爾*胺碘酮 (口服)電復律 肺靜脈電隔離消融& 起搏+/-CRT心肌肥厚 心功能不全心肌缺血上游治療器器質質性心性心臟臟病病AF患者心律控制策略患者心律控制策略Circ J. 2008 ; 72 (Suppl.IV) : 15811638* 除外心功能不全 消融& 起搏= AV 結消融 + 心室起搏延遲外向 K 通道; IK (IKur, IKr, IKs)內(nèi)向整流 K 通道; IK1瞬時外向 K 通道; ItoATP-敏感性 K 通道; IK.ATP

3、乙酰膽堿-激活 K 通道channel; IK.ACh內(nèi) Na-激活 K 通道; IK.Na1 sec.IKr 阻滯阻滯劑劑在在NSR和迷走神和迷走神經(jīng)誘導經(jīng)誘導的的AF中中對對心房心房動動作作電電位位時時程的作用程的作用NSR AF+ +2007 AHA Late-Breaking Trial in OrlandoN Engl J Med 2008;358:2667基基線線特征特征% 患者患者心律控制心律控制組組N = 682心率控制心率控制組組N = 694男性78%85%年齡 (歲)66116711NYHA 分級: -32%31%主要的心臟疾病診斷: 冠狀動脈疾病 非缺血性心肌病 其它4

4、8%36%16%48%39%13%高血壓49%46%糖尿病22%20%左室 EF %, 均數(shù)標準差276276AF類型: 陣法性 / 持續(xù)性33% / 67%30% / 70%左房直徑, mm, 均數(shù)標準差497497住院病史: 因為 AF / 因為 CHF51% / 54%55% / 56%藥藥物治物治療療12月后月后% 患者患者心律控制心律控制組組N = 682心率控制心率控制組組N = 694p 值值胺碘酮82%7%0.0001索他洛爾1.8%0.3%多非利特0.4%0.2%阻滯劑80%88%0.0001地高辛51%75%0.0001維拉帕米 或 地爾硫卓1.8%3.3%0.0999AC

5、EI81%82%0.4103ARB16%13%0.0870利尿劑80%82%0.3710螺內(nèi)酯47%49%0.5071口服抗凝劑88%92%0.0306ASA34%31%0.3066他汀44%46%0.6141N Engl J Med 2008;358:2667心律控制組每次隨訪中，竇性心律確診率為 75-80% Vernakalant Hydrochloride 用于房顫快速轉復 三期，隨機，安慰劑對照試驗 AF：336 例 陣發(fā)性 220 (3h-7d) 持續(xù)性 116 (8d-45d) Circulation 2008; 117:1518-1525轉復率：37.6% vs 2.6% (p

6、心室 （ AF時） 電壓依賴性阻滯 對去極化細胞敏感 (心房心室)INaItoIKrIKsIKurIK1IKAChICaLNCXDronedaroneCelivaroneATI-2042VernakalantAZD7009TedisamilRanolazineLate INaAVE0118NIP-141/142XEN-D0101AVE1231 NTC-801Arora R et al.: J Am Coll Cardiol 49, 1340-1348 (2007)LAAPLAPVPLALAAP=0.04GIRK4GIRK1PLALAAPVAtrial-Selective K+ Channel

7、BlockerKrapivinsky G et al.: J Biol Chem 270, 28777-28779 (1995)Cha TJ et al. Circulation. 2006;113(14):1730-7.心衰引起心臟交感神經(jīng)通過gp130介導的細胞因子發(fā)生膽堿能分化Hideaki KanazawaDivision of Cardiology, Department of Internal Medicine, Regenerative Medicine and Advanced Cardiac TherapeuticsKeio University School of Medi

8、cine, Tokyo, Japan73rd Annual Scientific Meeting of the Japanese Circulation Society, Young Investigator AwardActininTHWild typeLIF transgenicscale bar 50 mLIF 心心臟臟特異性高表達特異性高表達導導致心致心臟臟交感神交感神經(jīng)經(jīng)神神經(jīng)遞質經(jīng)遞質的改的改變變CHTActininWTRelative epicardial nerve area1.00LIF-tg*0.51.5THCHT*LVLVLVLV*：p0.01scale bar 100

9、mChAT+/TH+ ratio 102003040*WTLIF-tg(%)ChAT Toto-3MergedTH Toto-3ChAT Toto-3MergedTH Toto-3*：p0.01LIF 心心臟臟特異性高表達增加星形神特異性高表達增加星形神經(jīng)節(jié)經(jīng)節(jié)的膽堿能特性的膽堿能特性 Stellate gangliaStellate gangliaWild typeLIF transgenicTH : sympatheticChAT : parasympathetic心衰患者心心衰患者心臟臟交感神交感神經(jīng)經(jīng)神神經(jīng)遞質經(jīng)遞質的改的改變變THCHTMergedscale bar 50 mLVLV

10、THCHTMergedNormalHeart failureRelative TH+ nerve area0.20.40.80Relative CHT+ nerve area20 5101500.625*1.01.2NormalHeart failureNormalHeart failure*：p0.01TH : sympathetic markerCHT : parasympathetic marker慢性 AF 患者中，獨立于激動劑的，心房-IK.ACh活性增高。 持續(xù)激活的 IK.ACh 增加心房發(fā)生心動過速的易感性，并維持 AF。心臟交感神經(jīng)膽堿能分化可能是 AF 的基質Pilsica

11、inideCibenzolinePropafenoneDisopyramideFlecainidePVIsolationAblate&PaceLone AFParoxysmal AFElectrical ConversionRate controlBepridil+/-AprindineSotalolAmiodarone (po)First choiceIn case of short AF durationSecond , third choiceRhythm Management Strategy for Patients With Lone AFCirc J. 2008 ; 72

12、 (Suppl.IV) : 15811638Persistent AFM2A1Na/KATPasePumpsCaKI fReceptorsPilsicainideFlecainideCibenzolinePropafenoneDisopyramideslowmedfastNaChannelsDrugAThe intensity of the action is indicated ( low, moderate, high ) AAAAProfiles of Antiarrhythmic Agentsin the Framework of the Sicilian GambitOgawa S:

13、 JPN. J. ELECTROCARDIOLOGY 17(2), 191, 1997Rate controlAprindineBepridilSotalol*Amiodarone (po)Electrical ConversionPVIsolationAblate& Pace+/-CRTHypertrophic heart Failed heartIschemic heartUpstream therapyRhythm Management Strategy for AF Patients With Organic Heart DiseaseCirc J. 2008 ; 72 (Su

14、ppl.IV) : 15811638* Excluding failed heart Ablate& Pace= AV nodal ablation + ventricular pacingdelayed outward K channel; IK (IKur, IKr, IKs)inward rectifier K channel; IK1transient outward K channel; ItoATP-sensitive K channel; IK.ATPacetylcholine-activated K channel; IK.AChinternal Na-activate

15、d Kchannel; IK.Na1 sec.Effect of IKr blocker on atrial action potential duration during NSR and vagally-inducedAFNSR AF+ +2007 AHA Late-Breaking Trial in OrlandoN Engl J Med 2008;358:2667Baseline Characteristics% of ptsRhythm Control GroupN = 682Rate Control GroupN = 694Male Sex78%85%Age (yrs)661167

16、11NYHA class: -32%31%Predominant cardiac diagnosis: Coronary artery disease Non-ischemic cardiomyopathy Other48%36%16%48%39%13%Hypertension49%46%Diabetes22%20%Left ventricular EF %, meanSD276276Type of AF: proxysmal / persistent33% / 67%30% / 70%Left atrial dimension, mm, meanSD497497Prior hospitali

17、zation: for AF / for CHF51% / 54%55% / 56%Medical Therapy at 12 months% of ptsRhythm Control GroupN = 682Rate Control GroupN = 694p ValueAmiodarone82%7%0.0001Sotalol1.8%0.3%Dofetilide0.4%0.2%Beta-blocker80%88%0.0001Digoxin51%75%0.0001Verapamil or diltiazem1.8%3.3%0.0999ACE inhibitor81%82%0.4103ARB16

18、%13%0.0870Diuretic80%82%0.3710Spironolactone47%49%0.5071Oral anticoagulant88%92%0.0306ASA34%31%0.3066Statins44%46%0.6141N Engl J Med 2008;358:2667Sinus rhythm was documented in 75-80% of patients in the rhythm control group at each visitVernakalant Hydrochloride for Rapid Conversion of Atrial Fibril

19、lation A Phase 3, Randomized, Placebo-Controlled Trial AF：336 cases paroxysmal 220 (3h-7d) persistent 116 (8d-45d) Circulation 2008; 117:1518-1525Conversion rate：37.6% vs 2.6% (pventricle during AF Voltage-dependent block Sensitive to depolarized cells (atriumventricle)INaItoIKrIKsIKurIK1 IKACh ICaL

20、 NCXDronedaroneCelivaroneATI-2042VernakalantAZD7009TedisamilRanolazineLate INaAVE0118NIP-141/142XEN-D0101AVE1231 NTC-801Arora R et al.: J Am Coll Cardiol 49, 1340-1348 (2007)LAAPLAPVPLALAAP=0.04GIRK4GIRK1PLALAAPVAtrial-Selective K+ Channel BlockerKrapivinsky G et al.: J Biol Chem 270, 28777-28779 (1

21、995)Cha TJ et al. Circulation. 2006;113(14):1730-7.Heart failure causes cholinergic transdifferentiation of cardiac sympathetic nerves via gp130-mediated cytokines Hideaki KanazawaDivision of Cardiology, Department of Internal Medicine, Regenerative Medicine and Advanced Cardiac TherapeuticsKeio Uni

22、versity School of Medicine, Tokyo, Japan73rd Annual Scientific Meeting of the Japanese Circulation Society, Young Investigator AwardActininTHWild typeLIF transgenicscale bar 50 mCardiac-specific overexpression of LIF induced neurotransmitter switching in the cardiac sympathetic nerve CHTActininWTRelative epicardial nerve area1.00LIF-tg*0.51.5THCHT*LVLVLVLV*：p0.01scale bar 100 mChAT+/TH+ ratio 102003040*WTLIF-tg(%)ChAT Toto-3MergedTH Toto-3ChAT Toto-3MergedTH Toto-3*：p0.01Cardiac-specific overexpression